Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia.

Hurkmans, EGE; Klumpers, MJ; Dello Russo, C; De Witte, W; Guchelaar, H-J; Gelderblom, H; Cleton-Jansen, A-M; Vermeulen, SH; Kaal, S; van der Graaf, WTA; Flucke, U; Gidding, CEM; Schreuder, HWB; de Bont, ESJM; Caron, HN; Gattuso, G; Schiavello, E; Terenziani, M; Massimino, M; McCowage, G; Nagabushan, S; Limaye, A; Rose, V; Catchpoole, D; Jorgensen, AL; Barton, C; Delaney, L; Hawcutt, DB; Pirmohamed, M; Pizer, B; Coenen, MJH; Te Loo, DMWM

Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia.

Hurkmans, EGE Klumpers, MJ Dello Russo, C De Witte, W Guchelaar, H-J Gelderblom, H Cleton-Jansen, A-M Vermeulen, SH Kaal, S van der Graaf, WTA Flucke, U Gidding, CEM Schreuder, HWB de Bont, ESJM Caron, HN Gattuso, G Schiavello, E Terenziani, M Massimino, M McCowage, G Nagabushan, S Limaye, A Rose, V Catchpoole, D

Jorgensen, AL Barton, C Delaney, L Hawcutt, DB Pirmohamed, M Pizer, B Coenen, MJH Te Loo, DMWM

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Publisher:: FRONTIERS MEDIA SA
Publication Type:: Journal Article
Citation:: Front Pharmacol, 2022, 13, pp. 980309
Issue Date:: 2022

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Field	Value	Language
dc.contributor.author	Hurkmans, EGE
dc.contributor.author	Klumpers, MJ
dc.contributor.author	Dello Russo, C
dc.contributor.author	De Witte, W
dc.contributor.author	Guchelaar, H-J
dc.contributor.author	Gelderblom, H
dc.contributor.author	Cleton-Jansen, A-M
dc.contributor.author	Vermeulen, SH
dc.contributor.author	Kaal, S
dc.contributor.author	van der Graaf, WTA
dc.contributor.author	Flucke, U
dc.contributor.author	Gidding, CEM
dc.contributor.author	Schreuder, HWB
dc.contributor.author	de Bont, ESJM
dc.contributor.author	Caron, HN
dc.contributor.author	Gattuso, G
dc.contributor.author	Schiavello, E
dc.contributor.author	Terenziani, M
dc.contributor.author	Massimino, M
dc.contributor.author	McCowage, G
dc.contributor.author	Nagabushan, S
dc.contributor.author	Limaye, A
dc.contributor.author	Rose, V
dc.contributor.author	Catchpoole, D https://orcid.org/0000-0001-5836-1413
dc.contributor.author	Jorgensen, AL
dc.contributor.author	Barton, C
dc.contributor.author	Delaney, L
dc.contributor.author	Hawcutt, DB
dc.contributor.author	Pirmohamed, M
dc.contributor.author	Pizer, B
dc.contributor.author	Coenen, MJH
dc.contributor.author	Te Loo, DMWM
dc.date.accessioned	2024-03-14T04:31:43Z
dc.date.available	2022-12-14
dc.date.available	2024-03-14T04:31:43Z
dc.date.issued	2022
dc.identifier.citation	Front Pharmacol, 2022, 13, pp. 980309
dc.identifier.issn	1663-9812
dc.identifier.issn	1663-9812
dc.identifier.uri	http://hdl.handle.net/10453/176704
dc.description.abstract	Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.
dc.format	Electronic-eCollection
dc.language	eng
dc.publisher	FRONTIERS MEDIA SA
dc.relation	University of Technology SydneyUTSCG09
dc.relation.ispartof	Front Pharmacol
dc.relation.isbasedon	10.3389/fphar.2022.980309
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1115 Pharmacology and Pharmaceutical Sciences
dc.subject.classification	3214 Pharmacology and pharmaceutical sciences
dc.title	Genome-wide analyses of platinum-induced ototoxicity in childhood cancer patients: Results of GO-CAT and United Kingdom MAGIC consortia.
dc.type	Journal Article
utslib.citation.volume	13
utslib.location.activity	Switzerland
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Computer Science
utslib.copyright.status	open_access	*
dc.date.updated	2024-03-14T04:31:42Z
pubs.publication-status	Published online
pubs.volume	13

Abstract:

Hearing loss (ototoxicity) is a major adverse effect of cisplatin and carboplatin chemotherapy. The aim of this study is to identify novel genetic variants that play a role in platinum-induced ototoxicity. Therefore, a genome-wide association study was performed in the Genetics of Childhood Cancer Treatment (GO-CAT) cohort (n = 261) and the United Kingdom Molecular Genetics of Adverse Drug Reactions in Children Study (United Kingdom MAGIC) cohort (n = 248). Results of both cohorts were combined in a meta-analysis. In primary analysis, patients with SIOP Boston Ototoxicity Scale grade ≥1 were considered cases, and patients with grade 0 were controls. Variants with a p-value <10-5 were replicated in previously published data by the PanCareLIFE cohort (n = 390). No genome-wide significant associations were found, but variants in TSPAN5, RBBP4P5, AC010090.1 and RNU6-38P were suggestively associated with platinum-induced ototoxicity. The lowest p-value was found for rs7671702 in TSPAN5 (odds ratio 2.0 (95% confidence interval 1.5-2.7), p-value 5.0 × 10-7). None of the associations were significant in the replication cohort, although the effect directions were consistent among all cohorts. Validation and functional understanding of these genetic variants could lead to more insights in the development of platinum-induced ototoxicity.

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http://hdl.handle.net/10453/176704